Indomethacin but not aspirin increases plasma lithium ion levels.

The pharmacokinetic drug interactions between lithium sulfate and the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin and aspirin were studied in ten normal female volunteers restricted to 150-mEq/day of sodium. Indomethacin decreased renal lithium ion elimination by 23% and caused a 40% increase in steady state plasma lithium ion levels. In contrast, aspirin had no effect on plasma lithium ion levels and increased renal lithium ion elimination by only 6%. Renal prostaglandin E2 excretion was suppressed by 50% to 60% of control levels by indomethacin and by 65% to 70% by aspirin. A clinically important drug interaction with the risk of lithium intoxication can occur between lithium salts and indomethacin. However, aspirin did not affect steady state plasma levels of lithium ion and thus may be preferable for antirheumatic treatment of patients undergoing long-term therapy with lithium salts. Frequent monitoring of plasma lithium ion levels is absolutely necessary in patients receiving both lithium salts and NSAIDs.

Effects of diclofenac on lithium kinetics.

The influence of the prostaglandin (PG) synthesis-inhibiting, nonsteroidal anti-inflammatory drug (NSAID) diclofenac on lithium kinetics was studied in five normal women on a 150-mEq sodium diet. Diclofenac decreased lithium renal clearance by 23% (P - 0.002) and increased lithium plasma levels by 26% (P - 0.001). Renal PG synthesis was suppressed by 53% of control values. These data show a clinically important drug interaction, possibly on the basis of a PG-dependent mechanism, with the risk of lithium intoxication for patients treated with lithium salts and NSAIDs.

Effects of cimetidine and ranitidine on steady-state propranolol kinetics and dynamics.

The influence of cimetidine (1000 mg daily, one day oral pretreatment) and ranitidine (300 mg daily by mouth, 1 and 6 days pretreatment) on steady-state propranolol (160 mg sustained-release capsule, once daily) plasma levels (Psss) and dynamic beta-blocker effects was assessed by bicycle ergometer exercise and isoproterenol sensitivity test in five normal subjects. During the 3 hr of the dynamic tests Psss were elevated from 25% to 67% by cimetidine, whereas Pss was unchanged by ranitidine. The estimated hepatic blood flow (EHBF) as calculated from indocyanine green (ICG) plasma clearance was only slightly reduced by 15 +/- 23% (mean +/- SD, n = 4) after one oral dose of 150 mg ranitidine and showed substantial intersubject variability. Dynamic parameters, like propranolol-induced heart rate and blood pressure changes under physical exercise or during the isoproterenol sensitivity test, were not influenced by ranitidine or cimetidine. Since our study was performed on normal subjects with relatively low propranolol doses these results do not rule out the risk of severe reinforcement of beta-adrenergic receptor blocking effects if propranolol and cimetidine are taken together by patients.

Chronopharmacokinetic study with prolonged infusion of midazolam.

Physiological and temporal variation in the disposition of midazolam has been reported. In order to delineate the underlying mechanisms of these alterations, we infused in 5 healthy male volunteers for 26 hours midazolam at a rate of 0.025 mg/kg/h preceded by a bolus of 0.05 mg/kg. Thus, steady-state conditions were rapidly achieved. Plasma levels of midazolam were monitored on a 2-hourly basis during this period. In addition, the pharmacodynamic response to the new sedative/hypnotic benzodiazepine was characterised by a pencil tracking test, sedation index formed from visual analogue scales, and choice reaction time. In all subjects, small (4 to 16%) but clinically irrelevant fluctuations of steady-state plasma concentrations around 45 ng/ml were observed. During the night-time (11pm to 7am) plasma concentrations were slightly (p = 0.074) higher than during the daytime. Total plasma clearance varied from 563 to 823 ml/min. Plasma protein binding of midazolam was time independent. Since in only 1 of 5 subjects was a circadian rhythm observed, fluctuations in plasma midazolam concentrations under controlled and constant conditions are probably not of clinical significance.

Pharmacodynamic interaction between midazolam and a specific benzodiazepine antagonist in humans.

The pharmacodynamic interaction between midazolam and the specific benzodiazepine antagonist Ro 15-1788 has been investigated in six healthy male volunteers. Hypnotic steady-state concentrations of midazolam (55 +/- 11 ng/mL; mean +/- SD) have been achieved rapidly by an intravenous bolus of 0.07 mg/kg and maintained by an individual but constant infusion rate of 0.025 to 0.04 mg/kg/hr for eight hours. Following a two-hour control period, the antagonist (2.5 mg) or the solvent were injected double-blind in random order. Three hours later, the other medication was administered. Whereas plasma levels of midazolam remained constant throughout the complete eight-hour trial (Clearance = 670 +/- 96 mL/min) concentrations of Ro 15-1788 declined rapidly with an elimination half-life between 0.7 and 1.8 hours and a total plasma clearance of 702 +/- 235 mL/min. Concentrations of Ro 15-1788 approached the analytic limit of 2 ng/mL within three hours. The pharmacodynamic response to midazolam and the antagonist was assessed by a sedation index using visual analogue scales, reaction time (RT) measurements, and transformed Fourier analysis of the power spectrum of the recorded electroencephalogram (EEG). About 30 to 45 seconds following the injection of Ro 15-1788, hypnotic action of midazolam was completely reversed as visualized by return to alpha rhythm in the EEG, shortening of prolonged RT, and normalization of the elevated sedation index. The antagonistic action lasted for about two to three hours. The abrupt arousal from sleep was not associated with any unpleasant sensations, however, three subjects experienced a profound perspiration for about ten minutes following the injection of Ro 15-1788.(ABSTRACT TRUNCATED AT 250 WORDS)

Practice effect of volunteers in repeated psychometric testing. How to handle this intervening variable in clinical pharmacology studies?

Performance in psychometric tests may show a practice effect with repeated testing. Ideally, a plateau of efficiency should be reached prior to first drug intake. In order to assess the period of familiarization in a multiple choice reaction task (MCRT) 17 healthy subjects practiced the test up to 36 times in the drug free run-in period of 2 trials. A tentative "inclusion criterion" was used in 7 subjects to decide whether their learning phase could be regarded as being finished. Seven to 20 training sessions were required for a first rapid learning phase. There were remarkable differences in the absolute performance of the subjects and in the time course of their practice effect. However, the time course of the learning phase was not dependent on the absolute performance level. By means of the tentative "inclusion criterion" it was possible to reject a subject with a low but highly variable performance. However, it was not stringent enough to indicate the final plateau of efficiency. More "drug free" data concerning the practice effect should be published to enable the users of psychometric tests to make a reasonable selection according to their needs and to help them design their trials properly.

Intra-subject variability of platelet alpha 2-adrenoceptor binding sites in healthy volunteers.

The specific alpha 2-adrenoceptor binding (Bmax and KD) of (3H-methyl)yohimbine to intact platelets of healthy young volunteers was not significantly different in 7 males and 7 females. Its extent was not dependent on the menstrual cycle. The intraindividual variability was relatively high with means between 6% and 38% for Bmax and between 10% and 39% for KD, respectively. An intra-assay variation of 5.4 to 12.4% for Bmax and of 5.1 to 19.6% for KD contributed to this variability. Therefore, drug effects on platelet alpha 2-adrenoceptor binding in intraindividual cross-over studies are evidential only if the drug-induced changes exceed the intra-subject variability. This should be examined by at least 3 estimates of pre-drug values.

[Risks of simultaneous tocolytic treatment with beta adrenergic and PG inhibiting agents]. / Risiken einer Tokolysebehandlung durch Kombination von Betaadrenergica und Prostaglandinsynthesehemmstoffen.

Betaadrenergics are the most important agents in the treatment of premature labour. Often they are used in combination with steroids which promote fetal lung maturation and prevent respiratory distress syndrome in preterm infants. Because PG synthesis inhibitors also reduce uterine contractions they have been used as tocolytics whenever beta adrenergics alone fail. Several cases of pulmonary edema in otherwise healthy pregnant women have been reported following a combined tocolytic treatment with betaadrenergic drugs and PG synthesis inhibitors. The inhibited synthesis and function of renal PGs may be a very important factor contributing to those fatal events. Both, the ADH stimulating effect of beta adrenergics and the inhibition of the negative feed back mechanism of PGs on ADH action by blockade of PG synthesis potentiates renal water retention, thereby increasing the risk of water intoxication. Concerning the effects of maternal tocolytic treatment on the fetus or newborn, there is good evidence that PG inhibitors like aspirin or indomethacin can lead to closure of the ductus Botalli prior to birth and persistent pulmonary hypertension of the newborn. Severe cardiopulmonary adaption disturbances may be the consequence. Routine clinical use of PG synthesis inhibitors in combination with adrenergic stimulants cannot be recommended on the basis of available information.

Mechanism of antihypertensive action of ketanserin in man.

A randomised double blind crossover study was carried out to determine whether ketanserin, a serotonin antagonist with an antihypertensive action in animals, has an alpha 1 adrenergic mediated antihypertensive effect in man. Steady state plasma ketanserin concentrations (mean 88 (SD 19) micrograms/1) and cardiovascular responses measured in five healthy volunteers showed that therapeutic doses of ketanserin significantly antagonised the alpha 1 receptor mediated increase in arterial blood pressure after treatment with methoxamine. Thus the antihypertensive action of ketanserin in man appears to originate from a blockade of peripheral vascular alpha 1 receptors.

Pharmacokinetic and pharmacodynamic interaction study of diazepam and metoprolol.

In 6 normotensive, healthy male volunteers the pharmacodynamic responses (blood pressure, heart rate; sedation index, tracking test, reaction time) to metoprolol (100 mg bid orally), diazepam (0.1 mg/kg intravenously) and to their combination were studied. The pharmacokinetics of diazepam were also compared in a cross-over experiment, with and without pretreatment by the beta-adrenoceptor antagonist to evaluate the possibility of a drug interaction. The pharmacodynamic and pharmacokinetic investigations indicated that metoprolol only slightly impaired the elimination of diazepam (18% decrease in total clearance, 25% increase in elimination half-life). The pharmacodynamics of metoprolol (17% decrease in heart rate, 17% decrease in diastolic RR) was not significantly altered by the bolus injection of diazepam. The extent of prolongation in choice reaction time (RT2) induced by diazepam was significantly (p = 0.001) more pronounced following the co-administration of metoprolol. However, the results of RT1, the tracking test and the sedation index did not indicate any increased effect due to the beta-blocking agent. It is concluded that concomitant treatment with metoprolol and diazepam causes only minor and clinically irrelevant changes in drug metabolism and drug response.

Drug interactions through binding to cytochrome p 450: the experience with h2-receptor blocking agents.

H2-receptor blocking agents, such as cimetidine, ranitidine or oxmetidine, are consumed in large amounts often together with a variety of other drugs. There is increasing evidence that cimetidine interferes with the hepatic elimination of several drugs, thereby aggravating the effects of the comedication. Microsomal studies in vitro revealed that cimetidine binds in therapeutic concentrations to cytochrome P450, which may represent the primary mechanism for its ability to inhibit drug metabolism and thereby interact with other drugs. The structurally different ranitidine (replacement of the imidazole in cimetidine by a furan ring) is about five times as potent as a H2-receptor blocker and displays low affinity for binding sites on cytochrome P 450. Therefore, therapeutic doses of ranitidine do not impair the metabolism of other drugs. Preliminary data with oxmetidine suggest that it too does not interfere at the level of hepatic elimination. Thus, it is concluded that new therapeutic agents should be tested for their ability to bind to cytochrome P 450 to determine possible risks of drug interactions.

Effect of intravenous ketanserin on plasma catecholamines and renin activity in normal volunteers.

In a placebo controlled, single blind, randomized cross over study catecholamines (CA) and renin activity (PRA) in plasma were measured in 2 female and 4 male healthy volunteers, at rest in the supine position, following a single intravenous injection of 0.15 mg/kg ketanserin (K) and placebo (P, 10 ml saline). K caused a significant increase in the area under the plasma norepinephrine (NE) time curve (AUCNE) from 13,200 to 18,100 ng X 1(-1) X min for 1 hour after the injection. The area under the plasma epinephrine (E) time curve (AUCE) was also increased but to a lesser extent; it was significantly elevated from 54 to 68 ng X 1(-1) X min for 1 minute after the injection. Dopamine (DA) and PRA did not show any significant response to ketanserin. Following the P injection, none of the four parameters showed any significant change.

Cimetidine increases steady state plasma levels of propranolol.

1 The influence of cimetidine (1000 mg daily) on propranolol steady state plasma levels has been studied in seven normal volunteers. Cimetidine was used as a 200 mg normal release tablet whereas propranolol was given as a 160 mg slow release formulation once daily. 2 After 1 day of cimetidine treatment (day 9 of the study) the mean (Css) and minimal (Css min) propranolol steady state plasma levels increased significantly from 24.1 +/- 14.9 ng/ml (mean +/- s.d.) to 39.2 +/- 27.7 ng/ml (P = 0.01) and from 14.8 +/- 9.3 ng/ml to 27.1 +/- 21.2 ng/ml (P = 0.03), respectively. The apparent oral clearance (Clo) was reduced from 6.7 +/- 4.3 l/min to 4.6 +/- 3.11/min (P = 0.006). 3 A prolongation of cimetidine administration to 5 days (day 13 of the study) intensified this effect significantly (P = 0.02): Css of propranolol was elevated from 23.2 +/- 14.4 ng/ml to 44.9 +/- 26.7 ng/ml (P = 0.003); Css min was increased from 14.1 +/- 10.2 ng/ml to 28.4 +/- 17.9 ng/ml (P = 0.02) while Clo decreased from 6.9 +/- 4.1 1/min to 3.3 +/- 1.61/min (P = 0.006). 4 We conclude that the drug interaction between propranolol and cimetidine leads to significant elevations of propranolol steady state plasma concentrations which may cause a clinically relevant enhancement of the effect of a given dosage. This requires careful observation of patients under concomitant treatment with propranolol and cimetidine.

Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man.

The pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 has been studied in 6 healthy male volunteers following a single intravenous dose of 2.5 mg. The drug was only slightly bound to plasma proteins (40 +/- 8%, mean +/- SD). A negligible amount (less than 0.2% of the dose) of unchanged drug was recovered in urine. Hepatic elimination was rapid, as shown by a short t1/2 of 0.9 +/- 0.2 h, and high total plasma and blood clearances of 691 +/- 216 ml/min and 716 +/- 199 ml/min, respectively. The fast decline of plasma levels from about 60 to 2 ng/ml accounts for the short-lasting reversal of benzodiazepine-induced sedation by Ro 15-1788.

Pharmacokinetics of ketanserin in man.

Kinetic data for the new antihypertensive agent ketanserin were determined in six healthy subjects after single oral (40 mg) or intravenous (0.15 mg/kg) doses. Plasma protein binding was 94.0 +/- 1.8% (mean +/- SD). Cumulative urinary excretion of unchanged drug was less than 4% within 48 h following the single dose. The maximal plasma level (Cmax) of 193 +/- 98.2 micrograms/l occurred within 0.5 to 4.0 h after oral intake. The ketanserin plasma level declined biexponentially after oral administration, and triexponentially over the 36 h following intravenous injection. The terminal elimination half-life (term. t 1/2) averaged 12.4 +/- 2.9 h and 12.8 +/- 4.8 h following oral and intravenous application, respectively. Total plasma clearance was 410 +/- 62.0 (i.v.) and 829 +/- 228 ml/min (p.o.) and the intravenous blood clearance averaged 602 +/- 91 ml/min, which indicates partly flow dependent hepatic elimination. A substantial first-pass effect led to a bioavailability of about 50% (range: 27-69%). Hepatic clearance of ketanserin followed the non-restrictive pattern. No change in blood pressure or heart rate was observed following ketanserin administration to normal volunteers.

Oxaprotiline: enantioselective noradrenaline uptake inhibition indicated by intravenous amine pressor tests but not alpha 2-adrenoceptor binding to intact platelets in man.

The optically active isomers of the racemic tetracyclic antidepressant oxaprotiline, R (-) oxaprotiline CGP 12,103 A (levoprotiline) and the S (+) oxaprotiline CGP 12,104 A, have been used as tools for a methodological Phase I study. Only the S (+) enantiomer CGP 12,104 A inhibits noradrenaline uptake. Intravenous amine pressor tests and ex vivo measurement of alpha 2-adrenoceptor binding to intact human platelets were compared with respect to their reliability in indicating CGP 12,104 A-induced amine uptake inhibition and possibly associated alpha 2-receptor down-regulation in healthy subjects. alpha 2-Adrenoceptor binding on intact human platelets did not distinguish between CGP 12,104 and CGP 12,103 A. However, amine pressor tests reflected the amine uptake inhibiting effect of CGP 12,104 A as a 5-fold decrease in tyramine pressor sensitivity and a 5-fold increase in noradrenaline pressor sensitivity.

Are prostaglandins involved in the antihypertensive effect of dihydralazine?

1. Two female and two male patients with essential hypertension were given dihydralazine plus saline or dihydralazine plus diclofenac intravenously on two separate occasions. The dihydralazine dose (range: 16.2--32.4 mg/2 h) was chosen individually to reduce systolic blood pressure by 20 mmHg from the control value before the investigation; the intravenous diclofenac dose was 75 mg/20 ml of saline for all patients. 2. Dihydralazine decreased diastolic blood pressure more than systolic blood pressure and increased heart rate; diclofenac reduced both of these effects. 3. Dihydralazine increased urinary volume and sodium clearance; both these effects were antagonized by concomitant treatment with diclofenac. 4. Whereas dihydralazine did not influence creatinine clearance appreciably, concomitant administration of diclofenac reduced creatinine clearance. 5. Urinary prostaglandin E2 was reduced by diclofenac. 6. We suggest that dihydralazine-mediated vasodilation is reduced by cyclo-oxygenase inhibition.

Influence of prostaglandin inhibition on dihydralazine induced acute effects in patients with essential hypertension.

In order to determine whether vasodilator prostaglandins (PG) contribute to the acute vascular and endocrine responses to intravenously administered dihydralazine, we examined its effects on systolic and diastolic blood pressure (BP), heart rate (HR), plasma renin activity (PRA) and the plasma catecholamines (CA) noradrenaline (NA), adrenaline (A) and dopamine (DA) as well as on sodium, potassium and creatinine clearance (CNa, CK and CCr respectively), urinary flow rate, urinary catecholamines (NA, A, DA) and iPGE2 and i6-keto-PGF1 alpha excretion rate in six patients (three females, three males) with essential hypertension before and after PG synthesis inhibition by the nonsteroidal, anti-inflammatory agent diclofenac. Diclofenac, which reduced urinary iPGE2 and i6-keto-PGF1 alpha excretion by 62% (P = 0.026) and 45% (P = 0.037), respectively, antagonized dihydralazine induced diastolic BP reduction (P = 0.0009), HR increase (P = 0.01), noradrenaline and adrenaline increase in plasma (P = 0.02 and P = 0.05, respectively), increase in urine flow rate (P = 0.03), sodium clearance (P = 0.01) and tended to reduce PRA. We conclude that dihydralazine-mediated changes can be reduced by cyclo-oxygenase inhibition, most likely on the basis of a reduction of its effect on peripheral resistance, thereby leading to less reflex activation of the sympathetic nervous and renin-angiotensin systems.

Influence of intravenous acetylsalicylic acid and sodium salicylate on human renal function and lithium clearance.

The influence of intravenous acetylsalicylic acid (ASA; D,L-lysine-mono-acetylsalicylate), equimolar doses of sodium salicylate (SA) and placebo (P) on renal function has been studied in 6 healthy female volunteers, in 150 mmol sodium balance, and in lithium (Li) steady state with a plasma Li between 0.6 and 0.8 mmol/l. Following a bolus injection of 0.5 g ASA, 0.444 g SA or P (50 ml saline) given over 10 min and a subsequent continuous infusion of 1.5 g ASA, 1.332 SA or P (150 ml saline) over 170 min, urine was collected for 3 h as well as 6 plasma samples at 30-min intervals. Plasma ASA levels were between 13.8 and 22.1 micrograms/ml and for SA they were 20.8 to 82.6 microgram/ml during ASA infusion, and between 22.5 and 108.9 microgram/ml for SA during SA infusion. Neither ASA nor SA caused a significant change in urine volume, in the renal clearances of Na, K, free water, osmolality, creatinine, inulin and p-aminohippurate (PAH) or in plasma Li level. Renal Li clearance was slightly reduced by SA, from 37.8 to 29.4 ml/min (p less than 0.05). Since renal prostaglandin (PG) synthesis (urinary PGE2 excretion) was 60.6% suppressed by ASA and was not affected by SA, the decrease in Li clearance cannot be related to inhibition of cyclooxygenase in the kidney.